We have developed GFScan(Gene Family Scan), a tool that identifies members of a gene family by searching genomic DNA sequences with genomic DNA motifs (or matrices) that are representative of the family. We have tested GFScan on four human gene families including the neurotransmitter-gated ion-channels (NGIC) family, the carbonic anhydrases (CA) family, the Dbl homology (DH) domain family, and the ETS-domain family. All known members of these families with motifs mapped to sequenced genomic DNA regions were found, whereas some novel genomic locations were also found to match the motifs, which may indicate new members in these families. Compared with other methods, GFScan recognized all true positives with much fewer false positives. We also showed that motifs constructed based on human genes could be used to search the mouse genome to identify orthologous family members in mouse. This program is available at http://www.cshl.org/mzhanglab/.